Small conductance Ca2+-activated K+ channels (SK channels) are gated directly by Ca2+ ions, via constitutively associated calmodulin (CaM). In many central neurons such as CA1 hippocampal neurons, SK channel activity underlies a medium component of the after hyperpolarization (mAHP) that follows an action potential, influencing the number of action potentials and the interspike interval during a burst of action potentials, thereby regulating neuronal excitability. In addition, SK channels in CA1 neurons modulate synaptic plasticity and alter memory encoding. Blocking SK channels reduces the stimulus intensity that is required to induce NMDA receptor-dependent long-term potentiation at Schaffer collateral synapses, and reduces the number of training trials required for hippocampal dependent learning. Therefore, modulators of SK channels will exert profound effects on integrated neuronal functions. We have found that a third protein, the serine/threonine protein kinase CK2, forms a stable and integral component of the SK2 channel complex. SK2-associated CK2 phosphorylates T80 of CaM and induces a shift in the Ca2+ sensitivity of SK2 channel gating. Additional data suggest that the N- and C-terminal domains of SK2 channels are in spatial proximity to the CaM binding domain, and all three domains interact with CK2. Further, the N-terminal domain is a strong activator of CK2, while the C-terminal domain contains numerous phosphorylation sites. The driving hypothesis for this application is that the N- and C-terminal domains of the SK2 channel regulate associated CK2 activity in response to dynamic metabolic signals and that SK2-associated CK2 activity influences neuronal excitability and the induction of synaptic plasticity. To test this hypothesis, we will identify the precise sites of interaction between SK2 and CK2 and determine the contributions of the N- and C-terminal domains to CK2 activity. We will determine high resolution structures of SK2-CaM-CK2 complexes. We will introduce CK2-independent SK2 channels into the CA1 area of SK2-null mice and determine the consequences for excitability and synaptic plasticity. These studies will employ a novel repertoire of reagents and techniques to engender an integrated understanding of multi-protein SK2 channel complexes, and their roles in fundamental aspects of neuronal excitability as well as synaptic plasticity. In addition, drugs that decrease SK2-associated CK2 activity and thereby decrease neuronal excitability may be therapeutic avenues for treatments of hyperexcitability disorders such as schizophrenia and epilepsy.